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Inhibition of Alzheimer’s BACE-1 by 2,6-dialkyl-4-chromon-3-yl-1,4-dihydropyridine-3,5-dicarboxylates

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Abstract

Alzheimer’s disease is the most common cause of dementia in the elderly, and no disease-modifying therapy is yet available for this devastating pathology. Deposition of different physicochemical forms of amyloid-β peptides is a critical phase in the pathogenesis of Alzheimer’s disease. β-Site amyloid precursor protein cleaving enzyme 1 (BACE-1) is a major enzyme responsible for amyloid-β production; therefore, inhibition of this enzyme represents a promising approach for the discovery of amyloid-β-lowering agents. In this study, a series of novel 2,6-dialkyl-4-chromon-3-yl-1,4-dihydropyridine-3,5-dicarboxylates (14–23) were synthesized and assessed as BACE-1 inhibitors using the Förster resonance energy transfer-based enzyme assay. Synthesized dihydropyridines exhibited weak-to-relatively-good BACE-1 inhibitory activities. Enzyme inhibitory activities ranged from 6.84 ± 6.62 (23) to 51.32 ± 1.04 (14) percent enzyme inhibitions at the concentration of 10 μM. The structure–activity relationship study showed that the presence of 4-[7-(ethanoyloxy)-4-oxo-4H-chromen-3-yl] moiety at C4 position of dihydropyridine ring (14, 16 and 18) confers higher activity compared with other substitutions at this position. Docking simulation predicted a key H-bond interaction between Asp32 residue and dihydropyridine NH group. Moreover, all docked dihydropyridines made good hydrophobic contacts with S1 and S2 subpockets of BACE-1. A good correlation between estimated binding affinities (pKi) and experimental BACE-1 inhibitory activities at 10 μM was obtained (R 2 = 0.639). The findings of this study suggested that 2,6-dialkyl-4-chromon-3-yl-1,4-dihydropyridine-3,5-dicarboxylates could be promising scaffolds for the discovery of novel BACE-1 inhibitors for management of Alzheimer’s disease.

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Acknowledgments

The authors wish to thank the Vice-Provost for Research of the Shiraz University of Medical Sciences for the financial support to this project (Grant Number: 93-01-12-8102).

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Authors and Affiliations

  1. Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran

    Nima Razzaghi-Asl

  2. Drug and Advanced Sciences Research Center, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran

    Nima Razzaghi-Asl

  3. Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi, 110 007, India

    Neha Aggarwal, Smriti Srivastava, Virinder S. Parmar & Ashok K. Prasad

  4. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, 71348-53734, Shiraz, Iran

    Ramin Miri & Omidreza Firuzi

  5. Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, P. le Aldo Moro 5, 00185, Rome, Italy

    Luciano Saso

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  1. Nima Razzaghi-Asl
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  2. Neha Aggarwal
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  8. Omidreza Firuzi
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Correspondence to Omidreza Firuzi.

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Razzaghi-Asl, N., Aggarwal, N., Srivastava, S. et al. Inhibition of Alzheimer’s BACE-1 by 2,6-dialkyl-4-chromon-3-yl-1,4-dihydropyridine-3,5-dicarboxylates. Med Chem Res 24, 3230–3241 (2015). https://doi.org/10.1007/s00044-015-1367-z

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